Methods for delivery of therapeutic materials to treat cancer

ABSTRACT

Disclosed is a localized method for treatment of cancer including the steps of providing a drug delivery catheter; navigating the catheter to the bile duct; and delivering a therapeutic agent into the bile duct. According to one aspect of the method, the drug delivery catheter is a multi-occlusion balloon catheter. The multi-occlusion balloon catheter may include at least two balloons. The multi-occlusion balloon catheter may optionally include a pressure transducer between the balloons to optimize delivery technique.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/685,950, filed Nov. 15, 2019, now U.S. Patent Application PublicationNo. 2020/0206481, which is a continuation of U.S. patent applicationSer. No. 15/351,922, filed Nov. 15, 2016, now U.S. Pat. No. 10,512,761,which is a continuation-in-part of U.S. patent application Ser. No.14/958,415, filed Dec. 3, 2015, now abandoned, which is acontinuation-in-part of U.S. patent application Ser. No. 14/870,833,filed Sep. 30, 2015, now U.S. Pat. No. 9,463,304, which is acontinuation of U.S. patent application Ser. No. 14/293,603, filed Jun.2, 2014, now U.S. Pat. No. 9,457,171, which claims priority to and thebenefit of U.S. Provisional Patent Application No. 61/830,218, filedJun. 3, 2013. U.S. patent application Ser. No. 14/293,603 is also acontinuation-in-part of U.S. patent application Ser. No. 12/958,711,filed Dec. 2, 2010, now U.S. Pat. No. 8,821,476, which claims priorityto and the benefit of U.S. Provisional Patent Application No.61/265,845, filed Dec. 2, 2009, each of the disclosures of which isincorporated herein by reference in its entirety.

BACKGROUND

The embodiments described herein relate generally to methods fordelivering a therapeutic material to treat pancreatic cancer.

Pancreatic cancer is considered an almost chemoresistant tumor. Theineffective result of systemic chemotherapy is at least in part due toan insufficient drug concentration within the tumor because ofdose-limited toxicity in bone marrow and epithelial tissue. Sincesystemic chemotherapy is limited its effectiveness, localized therapycan be desirable for advanced pancreatic cancer patients. For example,one such treatment can include local intra-arterial delivery ofchemotherapy. Intra-arterial infusion allows higher drug concentrationto reach the tumor, overcoming the problem of poor blood flow to tumormass in comparison to healthy tissue. Furthermore, intra-arterialchemotherapy can also take advantage of the first pass effect ofchemotherapeutics, generating higher-level drug concentrations at thetumor cell membrane and therefore, enhancing cellular drug uptake ascompared to intravenous infusion. Lastly, local delivery can reducesystemic side effects.

Such a chemotherapy treatment is usually administered through cathetersplaced in the celiac/hepatic artery or portal vein, however, a best modeof catheter placement has yet to be established. The tumor responserates of pancreatic arterial infusion chemotherapy can range widely, forexample, from 7% to 65%, at least in part due to efficacy of drugdelivery where anticancer drugs were administered via the celiac arterywithout assessment of drug distribution. Thus, a need exists forimproved methods for delivering a treatment such as a biologic agentand/or drug formation to target tissue of the pancreas, as well ashepatic tumors and cholangiocarinoma.

SUMMARY OF THE DISCLOSURE

Disclosed is a localized method for treatment of cancer, comprising thesteps of: providing a drug delivery catheter; navigating the catheter tothe bile duct; delivering a therapeutic agent into the bile duct.

According to one aspect of the aforementioned method, wherein the drugdelivery catheter is a multi-occlusion balloon catheter. Themulti-occlusion balloon catheter may comprise at least two balloons. Themulti-occlusion balloon catheter may optionally include a pressuretransducer between the balloons to optimize delivery technique.

According to one aspect of the aforementioned method, the therapeuticagent is selected from the group (5-fluorouracil (5-FU), Aldesleukin,Axitinib, Bleomycin, Carboplatin, Cetuximab, Cisplatin,Cyclophosphamide, Dacarbazine, Doxorubicin Hydrochloride, doxorubicinliposomal non-pegylated (un-coated), doxorubicin liposomal pegylated(PEG coated), Floxuridine, Gemcitabine Hydrochloride, IrinotecanHydrochloride Liposome, Lanreotide Acetate, leucovorin (antidote tofolic acid antagonist used with 5FU), Methotrexate, Mitomycin,Mitoxantrone, Nivolumab, Olaparib, Oxaliplatin, Sorafenib Tosylate,Temsirolimus, Thiotepa, Topotecan Hydrochloride, Vinblastine Sulfate,vincristine sulfate).

According to one aspect of the aforementioned method, the navigatingstep includes navigating the catheter using ERCP.

According to one aspect of the aforementioned method, the navigatingstep includes navigating the catheter to the bile duct percutaneously.

According to one aspect of the aforementioned method, the localizedmethod is used to treat pancreatic cancer.

According to one aspect of the aforementioned method, the localizedmethod is used to treat at least one of hepatic tumors andcholangiocarinoma.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an illustration of a pancreas and related structure in ahuman;

FIGS. 2 and 3 are schematic illustrations of a multi-occlusion catheterinsertion device according to an embodiment, in a first configurationand a second configuration, respectively;

FIG. 4 is a side view of a multi-occlusion catheter insertion deviceaccording to an embodiment, shown in a dilated configuration;

FIG. 5 is a side view of a portion of the multi-occlusion catheterinsertion device of FIG. 4 ; and

FIGS. 6-11 are each a cross-sectional view of a different portion of themulti-occlusion catheter insertion device of FIG. 4 , taken along lines6-6, 7-7, 8-8, 9-9, 10-10, and 11-11, respectively, in FIG. 5 .

FIG. 12 is a side view of a multi-occlusion catheter insertion deviceaccording to an embodiment.

FIG. 13 is a side view of a portion of the multi-occlusion catheterinsertion device of FIG. 12 .

FIGS. 14-19 are each a cross-sectional view of a different portion ofthe multi-occlusion catheter insertion device taken along lines 14-14,15-15, 16-16, 17-17, 18-18, and 19-19, respectively, in FIG. 13 .

FIG. 20 is a top view of a multi-occlusion catheter insertion deviceaccording to an embodiment, in a first configuration.

FIG. 21 is a side view of a handle included in the multi-occlusioncatheter insertion device of FIG. 20 .

FIG. 22 is a top view of a handle included in the multi-occlusioncatheter insertion device of FIG. 20 .

FIG. 23 is an enlarged cross-sectional view of a portion of the handleof FIG. 21 , indicated by the region X1 and taken along the line 23-23in FIG. 22 .

FIG. 24 is a cross-sectional view of a portion of the multi-occlusioncatheter insertion device of FIG. 20 , taken along the line 24-24.

FIG. 25 is an enlarged cross-sectional view of a portion of the handleof FIG. 21 , indicated by the region X2 and taken along the line 25-25in FIG. 22 .

FIG. 26 is a cross-sectional view of a portion of the multi-occlusioncatheter insertion device of FIG. 20 , taken along the line 26-26.

FIG. 27 is a cross-sectional view of a portion of the multi-occlusioncatheter insertion device of FIG. 20 , taken along the line 27-27.

FIG. 28 is a cross-sectional view of a portion of the multi-occlusioncatheter insertion device of FIG. 20 , taken along the line 28-28.

FIG. 29 is a top view of the multi-occlusion catheter insertion deviceof FIG. 20 in a second configuration.

FIG. 30 is an illustration of a portion of the multi-occlusion catheterinsertion device of FIG. 20 in use within a portion of a body.

FIG. 31 is a flowchart illustrating a method for treating the pancreas,according to an embodiment.

DETAILED DESCRIPTION

Methods described herein can be used, for example, for the insertion andmanipulation of a multi-occlusion catheter device to deliver therapeuticagents to the bile duct for treatment of pancreatic cancer or otherlocalized cancer. Tumors localized around the bile duct (cancer of thepancreatic head, primary and secondary liver tumors, andcholangiocarcinoma) may benefit from localized delivery through the bileduct itself. The bile duct can be exogenously accessed through anendoscopic retrograde cholangiopancreatogram (ERCP) catheter, one canenvision delivery of a double balloon catheter into the bile duct usingestablished ERCP technique. After localizing the double balloon catheterto the area of bile duct involved/adjacent to the tumor, that area ofbile duct is isolated by inflating the two balloon elements.Chemotherapeutic elements are then infused between the two balloons. Byincreasing the pressure between two balloon elements to exceed theinterstitial tissue pressure, in a diffusion dependent manner, thechemotherapeutic agent will then diffuse out the wall of the bile ductand into the tissue.

By monitoring and/or adjusting the pressure between the balloons, onecan change the penetration depth of the chemotherapy into the tissue.

According to some embodiments, a therapeutic material for treatment ofpancreatic cancer or other localized cancer is delivered into the bileduct using the multi-occlusion catheter. The gall bladder is connectedto the pancreas via the common bile duct. Localized delivery to the siteof the tumor has advantages for both maximizing local drug concentrationat the tumor site, and decreasing systemic side effects/toxicity. Thusthe approach disclosed herein may avoid some of the toxicity relatedside effects of delivering chemotherapy drugs directly to the pancreasand may enable the use of more concentrated dosage of chemotherapydrugs. It should be understood that therapeutic particles may besubstituted for or used in conjunction with chemotherapy drugs.Moreover, it should be understood that in some cases it may be useful toplace a stent to open the bile duct prior to delivering the chemotherapyand/or therapeutic agent.

By way of example, such a use can include navigating a catheter such asa multi-occlusion catheter to the target anatomy using conventionalpercutaneous approaches or the same approach used for endoscopicretrograde cholangiopancreatogram (ERCP), isolating the bile duct, andthen exogenously introducing therapeutic cells/agents/biologics into theisolated area, via an infusion port of the catheter. In such fashion,the cells/agents biologics can be delivered to the bile duct with highefficiency. In some embodiment, a device with two sliding ballooncatheters can be used to isolate bile duct. The isolated area can thenbe perfused with cells/therapeutic agents via an infusion port disposedbetween the two balloon catheters. In some embodiments, the devicesdescribed herein can be arranged such that a user can manipulate aportion of the device substantially single handedly, to allow foraccurate delivery of a biological agent and/or drug formulation to anisolated segment or portion of an organ.

This application incorporates by reference to co-pending U.S.application Ser. No. 14/958,415 filed on Dec. 3, 2015.

In some embodiments, an apparatus includes a handle, an inner catheter,an outer catheter, an actuator, a first occlusion element, and a secondocclusion element. The inner catheter is coupled to the handle and thefirst occlusion element is coupled to the inner catheter. The innercatheter defines an inner catheter lumen that is configured to receive aguidewire. The outer catheter is coupled to the housing and the secondocclusion element is coupled to the outer catheter. The outer catheterdefines a first lumen that is in fluid communication with a distalopening and is configured to introduce a therapeutic agent through thedistal opening into the bile duct. The outer catheter defines a secondlumen that is configured to receive at least a portion of the innercatheter.

The actuator is coupled to the handle and is configured to move theouter catheter relative to the handle. The second occlusion element isdisposed proximal to the first occlusion element and a distancetherebetween is adjustable when the outer catheter is moved relative tothe handle by the actuator.

In some embodiments, an apparatus includes a handle, an inner catheter,an outer catheter, a first occlusion element, a second occlusionelement, and an actuator. The inner catheter is coupled to the handleand the first occlusion element is coupled to the inner catheter. Theouter catheter is coupled to the housing and the second occlusion memberis coupled to the outer catheter. The outer catheter defines a firstlumen that is in fluid communication with a distal opening and that isconfigured to introduce a therapeutic agent therethrough and into thebile duct. The outer catheter defines a second lumen that is configuredto receive at least a portion of the inner catheter. The secondocclusion element is disposed proximal of the first occlusion element.The actuator is coupled to the handle and is configured to move theouter catheter relative to the handle between a first position in whichthe second occlusion element is at a first distance from the firstocclusion element and a second position in which the second occlusionelement is at a second distance from the first occlusion element, withthe second distance being greater than the first distance.

In some embodiments, a system and/or device(s) is provided forendovascular introduction of therapeutic materials selectively to thebile duct for the treatment of pancreatic cancer. In some embodiments, adevice and/or system can include, for example, an inner catheter havinga distal retractable occlusion element and an inner catheter lumenadapted and configured to introduce a guidewire, and an outer catheterhaving a distal retractable occlusion element, an infusion lumen adaptedand configured to introduce therapeutic materials to the bile duct, anda lumen for slidably receiving the inner catheter. In such anembodiment, the distal retractable occlusion element of the outercatheter can be positioned proximal to the distal retractable occlusionelement of the inner catheter; and a sealing element can be includedthat is configured to selectively isolate or seal an end of the outercatheter to prevent therapeutic materials from entering into the lumenof the outer catheter in which the inner catheter is slidably disposed.

In some embodiments, a selective sealing element can include, forexample, a ring, a membrane, or any other suitable element configured toprevent loss of therapeutic material into the lumen of the outercatheter in which the inner catheter is disposed. The lumen provided inthe inner catheter can be configured to perfuse a distal organ beyondthe targeted isolation region of the artery.

In some embodiments, a distance between the proximal retractableocclusion element and the selective sealing element can be configuredfor external adjustment, thus allowing a user to customize the isolatedarea (between the two occlusion elements) to better target the bile ductduring delivery of biologics. The proximal retractable occlusion elementand the selective sealing element can have a cross-sectional diameter,for example, between 2-12 mm.

In some embodiments, the devices and methods described herein can beused for isolating the perfusion area of the gall bladder forintroduction of chemotherapy for treatment of pancreatic cancer, hepatictumors and cholangiocarinoma or other therapeutic agents targeted to thepancreas.

As used in this specification, the singular forms “a,” “an” and “the”include plural referents unless the context clearly dictates otherwise.Thus, for example, the term “a member” is intended to mean a singlemember or a combination of members, “a material” is intended to mean oneor more materials, or a combination thereof.

As used herein, the term “set” can refer to multiple features or asingular feature with multiple parts. For example, when referring to aset of ports, the set of ports can refer to a single port or to multipleports.

As used herein, the words “proximal” and “distal” refer to a directioncloser to and away from, respectively, an operator of, for example, amedical device. Thus, for example, the end of the medical device closestto the patient's body (e.g., contacting the patient's body or disposedwithin the patient's body) would be the distal end of the medicaldevice, while the end opposite the distal end and closest to, forexample, the user of the medical device, would be the proximal end ofthe medical device. Said another way, the distal end portion is the endthat is located furthest from a point of reference, such as an origin ora point of attachment. For example, the distal end portion would be theend farthest away from a user's hand. The proximal end portion, thus,would be the position nearer to a point of reference such as an origin,i.e., the user's hand.

Table 1 is a list of chemotherapy drugs which may be delivered to thebile duct according to the method of the present invention.

TABLE 1 Trade Common Solvents/ # Drug Name(s) Indication(s) Diluents 15-fluorouracil 5FU, Breast, Liver, water (5-FU) Flourouracil,Pancreatic, Adrucil Stomach 2 Aldesleukin Proleukin Kidney water 3Axitinib Inlyta Kidney water 4 Bleomycin Blenoxane Cervical, waterTesticular 5 Carboplatin Paraplatin Ovarian water 6 Cetuximab ErbituxColorectal, water Head, Neck 7 Cisplatin Platinol-AQ Bladder, Liver,water Ovarian, Pancreatic, Testicular 8 Cyclo- Cytoxan Breast, Ovarian,water phosphamide Pancreatic 9 Dacarbazine DTIC-Dome Pancreatic water 10Doxorubicin Adriamycin, Breast, Liver, water Hydrochloride Rubex,Ovarian, (pH = 3) Caelyx Pancreatic, Stomach 11 doxorubicin MyocetBreast, Liver, water liposomal, non- Ovarian, (pH = 3) pegylated (un-Pancreatic, coated) Stomach 12 doxorubicin Doxil Breast, Liver, waterliposomal, Ovarian, (pH = 3) pegylated (PEG Pancreatic, coated) Stomach13 Floxuridine FUDR Liver, Pancreatic water 14 Gemcitabine Hospira,Breast, Ovarian, water Hydrochloride Gemcitab, Pancreatic (pH = 3)Gemzar 15 Irinotecan Onivyde, Pancreatic water Hydrochloride Camptosar(pH = 3) Liposome 16 Lanreotide Somatuline Pancreatic water Acetate 17leucovorin Depot Pancreatic water or (antidote to oral folic acidantagonist used with 5FU) 18 Methotrexate Otrexup, Breast, waterRheumatrex, Pancreatic Trexall 19 Mitomycin Mutamycin, Liver, water MMC,Pancreatic, Mitomycin C, Stomach Mitozytrex 20 Mitoxantrone NovantronePancreatic water 21 Nivolumab Opdivo Kidney water 22 Olaparib LynparzaOvarian water 23 Oxaliplatin Elotaxin Pancreatic water 24 SorafenibNexavar Kidney water Tosylate 25 Temsirolimus Torisel Kidney water 26Thiotepa Bladder, water Ovarian 27 Topotecan Hycamtin Cervical, waterHydrochloride Ovarian (pH = 3) or oral 28 Vinblastine Velban, Breast,water Sulfate Velsar Pancreatic, Testicular 29 vincristine Alcrist,Pancreatic water sulfate Biocristin, Oncocristin- AQ, VCR

FIG. 1 illustrates the liver 10, the gall bladder 20, and the pancreas30 situated within an abdominal cavity (not shown) of a mammal (e.g., ahuman). The pancreas 30 is a gland organ which is part of the digestiveand endocrine system of vertebrates. The pancreas 30 is both anendocrine gland producing hormones, including insulin, glucagon, andsomatostatin, as well as an exocrine gland, secreting pancreatic juicecontaining digestive enzymes that pass to the small intestine. Theseenzymes help in the further breakdown of the carbohydrates, protein, andfat in the chyme.

As shown, the common bile duct leads from the gall bladder to thepancreas 30.

FIGS. 2 and 3 are schematic illustrations of a multi-occlusion catheterinsertion device 100 useful for delivering therapeutic agents to thebile duct for treatment of pancreatic cancer. The multi-occlusioncatheter insertion device 100 (also referred to herein as “device”) canbe arranged to allow for substantially single handed use to, forexample, isolate a segment of a bodily lumen such as the buke duct,thereby allowing a procedure to be performed within the isolated segmentand/or allowing a targeted delivery of a biological or therapeuticagent. The device 100 includes a handle 110, an actuator 150, a firstcatheter 160, and a second catheter 170. The handle 110 can be anysuitable shape, size, or configuration. For example, in someembodiments, the handle 110 can have a shape and size that areconfigured to enhance the ergonomics of the device 100. As described infurther detail herein, the handle 110 can be grasped by a user to inserta portion of the first catheter 160 and a portion of the second catheter170 into a bodily lumen of a patient and can be manipulated to move,inflate, deflate, adjust, and/or otherwise reconfigure the portion ofthe first catheter 160 and the portion of the second catheter 170 withinthe bodily lumen. For example, the second catheter 170 can be movedrelative to the first catheter 160, or vice-versa, to adjust a distancebetween a first occlusion element 168 coupled to a distal end portion ofthe first catheter 160 and a second occlusion element 178 coupled to adistal end portion of the second catheter 170. The device 100 can beused to isolate a segment of the bile duct within the space definedbetween the first occlusion element 168 and the second occlusion element178. Thus, a procedure can then be performed within the isolated segmentsuch as for example, delivering a therapeutic agent to the isolatedsegment.

The handle 110 has a proximal end portion 111 and a distal end portion112. As described in further detail herein, the handle 110 can bearranged to enclose, house, and/or be disposed about a portion of thefirst catheter 160 and the second catheter 170. For example, the firstcatheter 160 and the second catheter 170 can each be coupled to thehandle 110. A first port 120 and a second port 125 (collectivelyreferred to herein as a first set of ports 128) are each disposed at theproximal end portion 111 of the handle 110. The first port 120 and thesecond port 125 can each define a lumen (not shown in FIGS. 2 and 3 ).In some embodiments, the first port 120 and the second port 125 can beformed monolithically or integrally with the first catheter 160. Thefirst port 120 and the second port 125 can be any suitable size, shape,or configuration. For example, in some embodiments, the first port 120and the second port 125 can extend from the proximal end portion 111 ofthe housing 110 such that at least a portion of the first port 120 andthe second port 125 is accessible outside of the handle 110. Althoughnot shown in FIGS. 2 and 3 , the first port 120 and the second port 125can each be physically and fluidically coupled to a device, mechanism,and/or the like, such as, for example, a source of an inflation mediumas described in more detail below. For example, in some embodiments, thefirst port 120 and the second port 125 can each include a Luer-Lok® orthe like that can physically and fluidically couple the first port 120and/or the second port 125 to such a device. As described in furtherdetail herein, the first set of ports 128 can be in fluid communicationwith at least a portion of the first catheter 160 to place at least theportion of the first catheter 160 in fluid communication with a device(e.g., a source of an inflation medium) coupled to the handle 110 viathe first port 120 and/or the second port 125. For example, the lumen ofthe first port 120 can be in fluid communication with a first lumendefined by the first catheter 160 and the lumen of the second port 125can be in fluid communication with a second lumen defined by the firstcatheter 160.

The distal end portion 112 of the handle 110 includes a third port 130,a fourth port 135, and a fifth port 140 (collectively referred to hereinas a second set of ports 143). The second set of ports 143 can be anysuitable arrangement such as, for example, described above withreference to the first set of ports 128. For example, the third port130, the fourth port 135, and the fifth port 140 can each define a lumen(not shown in FIGS. 2 and 3 ) and can each include a Luer-Lok® or thelike that can physically and fluidically couple the third port 130, thefourth port 135, and/or the fifth port 140 to any suitable attachment,device, mechanism, and/or the like. For example, the third port 130, thefourth port 135, and/or the fifth port 140 can each be coupled to anexternal device such as a device supplying a therapeutic agent, a devicesupplying an inflation medium or a device supplying an irrigationsolution as described in more detail below with reference to, forexample, device 400. In some embodiments, the second set of ports 143includes the fifth port 140 and only one of the third port 130 and thefourth port 135.

As described in further detail herein, the second set of ports 143 canbe in fluid communication with at least a portion of the second catheter170 to place at least the portion of the second catheter 170 in fluidcommunication with such external devices coupled to the handle 110 viathe third port 130, the fourth port 135, and/or the fifth port 140. Forexample, the third port 130 and/or the fourth port 135 can be coupled toand in fluid communication with a first lumen defined by the secondcatheter 170, and the fifth port 140 can be coupled to and in fluidcommunication with a second lumen defined by the second catheter 170. Insome embodiments, the third port 130, the fourth port 135, and/or thefifth port 140 can be monolithically or integrally formed with thesecond catheter 170. Moreover, the second set of ports 143 can becoupled to or operably coupled to the actuator 150 as described in moredetail herein.

The first catheter 160 (also referred to herein as “inner catheter”) andthe second catheter 170 (also referred to herein as “outer catheter”)can be any suitable catheter device. For example, in some embodiments,the first catheter 160 and the second catheter 170 are multi-lumencatheters. As shown in FIG. 2 , the first catheter 160 has a proximalend portion 161 and a distal end portion 162. The proximal end portion161 of the first catheter 160 is disposed within a portion of the handle110. More specifically, the proximal end portion 161 of the firstcatheter 160 can be fixedly disposed within the portion of the handle110 to place the first catheter 160 in fluid communication with one ormore of the ports 120 and 125 of the first set of ports 128. In someembodiments, the first catheter 160 can define a first lumen that can bephysically and fluidically coupled to the first port 120 and a secondlumen that can be physically and fluidically coupled to the second port125. In other embodiments, a first catheter can be coupled to the handleand can be operably coupled to a first port and a second port (e.g.,ports 120, 125) via an intervening structure such as, for example,flexible tubing or the like. In this manner, the first port 120 can beplaced in fluid communication with a first lumen (not shown in FIGS. 2and 3 ) defined by the first catheter 160, as described in furtherdetail herein. Similarly, the second port 125 can be placed in fluidcommunication with a second lumen (not shown in FIGS. 2 and 3 ) definedby the first catheter 160. In some embodiments, the second port 125 andthe second lumen of the first catheter 160 can receive a guidewire orthe like, as described in further detail herein.

The distal end portion 162 of the first catheter 160 extends beyond adistal end portion of the handle 110 and includes the occlusion member168. The occlusion member 168 can be any suitable device or mechanismthat is configured to selectively limit, block, obstruct, or otherwiseocclude a bodily lumen in which the occlusion member 168 is disposed.For example, in some embodiments, the occlusion member 168 can be aninflatable balloon or the like that can be transitioned between acollapsed (e.g., deflated) configuration and an expanded (e.g.,inflated) configuration. In some embodiments, the arrangement of thefirst catheter 160 and the handle 110 can be such that the first port120 is in fluid communication with the occlusion member 168. Thus, inuse, the first port 120 can be fluidically coupled to a device that cansupply a pressurized fluid (e.g., air, inert gas, or liquid) to theocclusion member 168 to transition the occlusion member 168 between acollapsed configuration and an expanded configuration, as described infurther detail herein.

The second catheter 170 of the device 100 has a proximal end portion 171and a distal end portion 172. As shown in FIGS. 2 and 3 , the secondcatheter 170 is movably disposed about a portion of the first catheter160. More specifically, the second catheter 170 can be, for example, amulti-lumen catheter and can be arranged such that the first catheter160 is movably disposed within a first lumen (not shown in FIGS. 2 and 3) defined by the second catheter 170. The proximal end portion 171 canbe movably disposed within the handle 110 such that a portion of thesecond catheter 170 is in fluid communication with the second set ofports 143. In some embodiments, the second catheter 170 can bephysically and fluidically coupled to the third port 130 and the fourthport 135, and/or the fifth port 140. In other embodiments, the secondcatheter can be disposed within a handle and can be operably coupled toone or more ports via an intervening structure such as, for example,flexible tubing or the like. In this manner, the third port 130 and/orthe fourth port 135 can be placed in fluid communication with the secondlumen (not shown in FIGS. 2 and 3 ) defined by the second catheter 170,as described in further detail herein; the fifth port 140 can be placedin fluid communication with a third lumen (not shown in FIGS. 2 and 3 )defined by the second catheter 170, as described in further detailherein.

The distal end portion 172 of the first catheter 170 extends beyond adistal end portion of the handle 110 and includes an occlusion member178. The occlusion member 178 can be any suitable device or mechanismthat is configured to selectively limit, block, obstruct, or otherwiseocclude a lumen in which the occlusion member 178 is disposed. Forexample, in some embodiments, the occlusion member 178 can besubstantially similar to the occlusion member 168 of the first catheter160. In some embodiments, the arrangement of the second catheter 170 andthe handle 110 can be such that the third port 130 and/or the fourthport 135 is in fluid communication with the occlusion member 178. Thus,in use, the third port 130 and/or the fourth port 135 can be fluidicallycoupled to a device that can supply a pressurized fluid (e.g., air,inert gas, or liquid) to the occlusion member 178 to transition theocclusion member 178 between a collapsed configuration and an expandedconfiguration, as described in further detail herein. In someembodiments, at least a portion of the occlusion member 178 can beselectively permeable to allow a biological agent to pass therethrough.Although not shown in FIGS. 2 and 3 , in some embodiments, the distalend portion 172 of the second catheter 170 can define one or moreopenings. In such embodiments, the fifth port 140 can be fluidicallycoupled to a device that can supply irrigation, therapeutic material oragents, biological agents, and/or the like to a volume or regiondisposed between the occlusion member 168 of the first catheter 160 andthe occlusion member 178 of the second catheter 170.

As described above, the actuator 150 of the device 100 can be operablycoupled to the second set of ports 143. For example, in someembodiments, the actuator 150 is included in and/or coupled to thehandle 110 and arranged relative to the second set of ports 143 to beoperably coupled thereto. The actuator 150 can be any suitable device,mechanism, assembly, etc. that is movable between a first positionrelative to the handle 110, associated with the device 100 in the firstconfiguration (FIG. 2 ), and a second position relative to the handle110, associated with the device 100 in the second configuration (FIG. 3). Furthermore, with the actuator 150 operably coupled to the second setof ports 143, the actuator 150 can be operable in moving the second setof ports 143 between a first position relative to the handle 110 (e.g.,the distal position) and a second position relative to the handle 110(e.g., the proximal position), as indicated by the arrow AA in FIG. 3 .Thus, when the second catheter 170 is coupled to the second set of ports143, the actuator 150 can also move the second catheter 170 relative tothe handle 110 and/or relative to the first catheter 160 as described inmore detail below.

In some embodiments, the actuator 150 can be a push or pull slide thatcan move within a track (not shown in FIGS. 2 and 3 ) defined by thehandle 110. In other embodiments, the actuator 150 can be coupled to anenergy storage device (e.g., a spring, compressed gas, etc.) that isconfigured to move the actuator 150. For example, the actuator 150 caninclude a push button that allows a spring to transition from acompressed configuration towards an uncompressed configuration to movethe actuator 150 relative to the handle 110. In other embodiments, aportion of the actuator 150 can be rotated to move the actuator 150between its first position and its second position relative to thehandle 110. With the second catheter 170 physically and fluidicallycoupled to the second set of ports 143 (as described above), themovement of the actuator 150 can move the second catheter 170 relativeto the handle 110. More specifically, the proximal end portion 171 ofthe second catheter 170 can be movably disposed within the handle 110(as described above) such that when the actuator 150 is moved from itsfirst position to its second position, the proximal end portion 171 ofthe second catheter 170 is moved from a first position relative to thehandle 110 (e.g., FIG. 2 ) to a second position relative to the handle110 (e.g., FIG. 3 ).

With the second catheter 170 movably disposed about the first catheter160, the movement of the actuator 150 moves the second catheter 170relative to the first catheter 160. For example, when the device 100 isin the first configuration, a first distance D1 is defined between theocclusion member 168 of the first catheter 160 and the occlusion member178 of the second catheter 170. Therefore, with the first catheter 160fixedly disposed within the handle 110, the movement of the secondcatheter 170 in the proximal direction (e.g., the AA direction)increases the distance between the occlusion member 168 of the firstcatheter 160 and the occlusion member 178 of the second catheter 170 toa second distance D2, as shown in FIG. 3 .

In use, a guidewire (not shown) can be inserted into the second port 125and through a lumen defined by the first catheter 160. In this manner,the guidewire can be advanced through a bodily lumen and the device 100can be manipulated to advance the first catheter 160 along the guidewireto place the distal end portion 162 of the first catheter 160 and thedistal end portion 172 of the second catheter 170 at a target locationwithin the bodily lumen. Once at the target location, the actuator 150can be moved in the AA direction (e.g., the proximal direction) todefine a desired distance between the occlusion member 168 of the firstcatheter 160 and the occlusion member 178 of the second catheter 170,thereby placing the device 100 in the second configuration (FIG. 3 ). Asdescribed above, an inflation source can be coupled to the second port125 of the first catheter 160 and the same inflation source or a secondinflation source can be coupled to the third port 130 and/or the fourthport 135 of the second catheter 170. With the desired distance definedbetween the occlusion members 168 and 178, the inflation source(s) canbe used to inflate the occlusion members 168 and 178. Thus, theocclusion members 168 and 178 can be transitioned from the collapsed(e.g., deflated) configuration to the expanded (e.g., inflated)configuration to substantially isolate a segment of the bodily lumendisposed therebetween. With the occlusion members 168 and 178substantially occluding the bodily lumen, a biological or therapeuticagent can be delivered to the substantially isolated segment via thefourth port 135. For example, the biological or therapeutic agent can bedelivered through the fourth port 135 into a lumen of the secondcatheter that is in fluid communication with the opening (see, e.g.,opening 479 in FIG. 20 ) defined by the distal end portion 172 of thesecond catheter 170. In some instances, the substantially isolatedsegment can be irrigated by coupling an irrigation source to the fifthport 140. Thus, the irrigation is delivered to the substantiallyisolated segment via the opening (described above) defined by the distalend portion 172 of the second catheter 170.

FIGS. 4-11 illustrate a dilation catheter 200 according to anembodiment. FIG. 4 is a side view of the dilation catheter device 200(also referred to herein as “catheter device”). In this embodiment,dilatation of two balloons is used to occlude a desired length of anartery such as, for example, the splenic artery 40 (see, e.g., FIG. 1 ).Specifically, the catheter device 200 includes a first catheter 260(also referred to herein as “inner catheter”) and a second catheter 270(also referred to herein as “outer catheter”), a first Y-adaptor 228(also referred to herein as “first set of ports”) and a second Y-adaptor243 (also referred to herein as “second set of ports”), a firstocclusion element 268 (also referred to herein as “dilation element”,“occluder,” or “distal occlusion element”), and a second occlusionelement 278 (also referred to herein as “dilation element”, “occluder,”or “proximal occlusion element”) each configured to occlude a portion ofan artery. The first occlusion element 268 is coupled to the firstcatheter 260 and the second occlusion element 278 is coupled to thesecond catheter 270.

The occlusion elements 268 and 278 can each be moved between a collapsedconfiguration (also referred to as “retracted configuration”) forinsertion of the catheter device 200 into a body of a patient (e.g.,into an artery) and an expanded configuration (also referred to as“dilated configuration” or “inflated configuration”) for occluding aportion of an artery. The occlusion elements 268 and 278 when in thecollapsed configuration have a smaller outer perimeter (or diameter)than when in the expanded configuration.

The catheter device 200 includes a distal end portion 212 and a proximalend portion 211. In this embodiment, the occlusion elements 268 and 278are expandable balloons coupled to an outer surface of the firstcatheter 260 and an outer surface of the second catheter 270,respectively, and are disposed at the distal end portion 212 of thecatheter device 200. The catheter device 200 is shown in a dilatedconfiguration in FIG. 4 with the occlusion elements 268 and 278 (i.e.,balloons) in their expanded configuration (i.e., inflated, dilated).

FIG. 5 is a side view of the distal end portion 212 of the catheterdevice 200 (e.g., a distal end portion of the first catheter 260 and thesecond catheter 270) and FIGS. 6-11 illustrate cross-sections at variouslocations along the distal end portion 212 of the catheter device 200 toillustrate the various lumens of the catheter device 200. As shown inFIGS. 6-11 , the first catheter 260 defines a first lumen 265 and asecond lumen 263 that each can extend a length of the first catheter260. The first lumen 265 can be configured to receive a guidewire 280(shown, for example, in FIG. 4 ). The second lumen 263 can be used tocommunicate an inflation medium to and from the first occlusion element268 via an aperture 264 in fluid communication with the first occlusionelement 268 (see, e.g., FIG. 10 ).

As shown, for example, in FIGS. 6 and 7 , the second catheter 270defines a first lumen 274, a second lumen 273, and a third lumen 276.The first lumen 274 can be used to communicate an inflation medium toand from the second occlusion element 278 via an aperture 275 in fluidcommunication with the second occlusion element 278 (see, e.g., FIG. 7). The second lumen 273 is configured to slidably receive at least aportion of the first catheter 260 therethrough, as shown in FIGS. 6-9 .The third lumen 276 can terminate and be in fluid communication with aninfusion aperture 279 near a distal end 272 of the second catheter 270(see, e.g., FIG. 8 ). The infusion aperture 279 can be used tocommunicate a cell/biological/therapeutic material to a desired locationwithin a body/artery of a patient.

The first Y-adaptor 228 is coupled to the first catheter 260 andincludes two ports 220 and 225, as shown in FIG. 4 . The port 220defines a lumen (not shown) that is in fluid communication with thefirst lumen 265 of the catheter 260 and can be used to communicate aninflation medium to the first occlusion element 268 through the secondlumen 263. For example, a source of an inflation medium (not shown) canbe coupled to the catheter device 200 via the port 220 of the firstY-adaptor 228. The port 225 defines a lumen (not shown) that is in fluidcommunication with the second lumen 263 of the first catheter 260 (see,e.g., FIGS. 6-11 ) and can be used for introduction of the guidewire 280into the second lumen 263.

The second Y-adapter 243 is coupled to the second catheter 270 andincludes three ports 230, 235 and 240, as shown in FIG. 4 . The port 230defines a lumen (not shown) that is in fluid communication with thesecond lumen 273 of the second catheter 270 (see, e.g., FIGS. 6-11 ) andcan receive the first catheter 260 therethrough. The port 235 defines alumen (not shown) that is in fluid communication with the first lumen274 of the second catheter 270 and can be used to communicate aninflation medium to and from the second occlusion element 278 in asimilar manner as described above for port 225 and lumen 263. The port240 defines a lumen (not shown) that is in fluid communication with thethird lumen 276 of the second catheter 270 (see e.g., FIG. 6-11 ) andcan be used to introduce cells/biological/therapeutic materials into andthrough the third lumen 276 and out through the infusion aperture 279.

The catheter device 200 can also include a seal element 285 (see, e.g.,FIG. 9 ) (also referred to a as a “seal”, “sealing element”, “selectivesealing element”, or “filter-ring”) disposed at or near a distal end 272of the second catheter 270. The seal element 285 can prevent the entryof cells and or biologics that have been injected into an artery fromflowing back into the lumen 273. By doing so, a maximum number of cellscan be delivered to the treatment area, and improve engraftmentefficiency. The seal element 285 can be for example, a ring, a membraneor other known sealing elements used in medical devices.

The slidable coupling of the first catheter 260 within the second lumen273 of the second catheter 270 allows a collective length of the firstcatheter 260 and the second catheter 270 to be adjusted by slidablymoving the first catheter 260 and the second catheter 270 relative toeach other. Because the first occlusion element 268 is coupled to thefirst catheter 260 and the second occlusion element 278 is coupled tothe second catheter 270, the slidable adjustment of the first catheter260 and the second catheter 270 can thus allow adjustment of a distancebetween the second occlusion element 278 and the first occlusion element268. The second lumen 273 of the second catheter 270 can be sized toreceive the first catheter 260 with sufficient clearance to allow forease of sliding/adjustment.

In use, the catheter device 200 can be placed at a desired locationwithin an artery, such as for example, within a splenic artery 40 (seee.g., FIG. 1 ) and used to infuse a cell/biological material to apancreas 30. A length of the first catheter 260 and the second catheter270 can be adjusted such that a selected portion (e.g., a pancreaticportion) of the splenic artery 40 is isolated between the firstocclusion element 268 and the second occlusion element 278. Acell/biologic material can be injected through the catheter device 200and into the isolated region of the splenic artery 40.

The infusion of a cell/biological agent can occur in the localizedregion surrounding the isolated region or segment of vessel 40. In someinstances, however, the presence of one or more additional,side-branching vessels forming a flow-restricting configuration in theisolated region of vessel 40 can allow infusion to occur in a largersemi-localized region. To allow the operator to accommodate the locationof these side branches to fall within the isolated region, the firstcatheter 260 can be configured such that it is slidably associated withthe second catheter 270 and the space between (e.g., distance between)occlusion elements 268 and 278 can be varied according to thecircumstances of the desired treatment. The positioning of the distalocclusion element 268 within an artery can be individualized based onthe specific anatomy to allow an enclosed or isolated area between thetwo occlusion elements 268 and 278 with a linear length ranging, forexample, from 3 cm to 22 cm.

The cells targeted to the pancreas 30 (see e.g., FIG. 1 ) can be infusedthrough infusion port 240, traverse through the third lumen 276, andexit through the infusion aperture 279 into the area isolated betweenthe two occlusion elements 268 and 278. The catheter device 200 can beconfigured to enable delivery of target cells, such as insulin producingbeta cells, and autologous stem cells (mesenchymal, bone marrow, andothers) to blood vessels in communication with the pancreas in situ. Theinfusion pressure in the isolated blood vessel region can be measuredwith pressure monitoring through the infusion lumen of the catheter(with a monometer (not shown) in line with infusion port 279). Thepressure in the third lumen 276 can be based on the size of the cellsbeing delivered, on the flow rate, the viscosity of the solution, and/orflow resistance of the third lumen 276 of second catheter 270. The flowresistance of the catheter device 200 can in turn be determined basedon, for example, the inner coating material, the size and the length ofthe third lumen 276, the size of the third port 240, and/or the size ofthe distal infusion aperture 279. The catheter device 200 can allow forrapid infusion of cells (e.g., up to 2 milliliter per second (ml/sec)).In some applications, the rapid infusion of cells can enhance uptake andeventual engraftment. Smaller aperture size (e.g., the infusion aperture279), lumen size (e.g., the third lumen 276), and increased flowresistance may cause “sludging” of cells, leading to poor intra-arterialflow and diminished uptake. Lastly, the infusion aperture 279 andluminal design of the catheter device 200 can be configured to minimizerisk of mechanical cell damage during the infusion process.

FIG. 12 illustrates an embodiment of a catheter device 300 that uses twofilter elements, instead of expandable balloons to occlude and isolatethe area of interest for infusion of cells or chemotherapeutic agents,without inhibiting the flow of plasma through the isolated area. Thefilter elements can be formed with, for example, a medical meshmaterial. The size of the pores of the filter elements can be, forexample, about 2 microns (μm) or less in length, which can inhibit cellsfrom passing through the filter element, but not impede serum/plasma andother components from passing through the filter element. The catheterdevice 300 can be used for the same or similar functions as describedabove for catheter device 200. For example, the catheter device 300 canbe used for introduction of cells or other biologic or therapeuticmaterial into a desired location within a patient's body, such as withina splenic artery.

The catheter device 300 includes a first catheter 360 and a secondcatheter 370 that can be slidably coupled together as described abovefor catheter device 200, a first Y-adaptor 328 (also referred to hereinas “first set of ports”) coupled to the first catheter 360, a secondY-adaptor 343 (also referred to herein as “second set of ports”) coupledto the second catheter 370, a first occlusion element 368 (also referredto herein as “dilation element”, “occluder”, “distal occlusion element”)and a second occlusion element 378 (also referred to herein as “dilationelement”, “occluder”, “proximal occlusion element”) to occlude a portionof an artery. The first occlusion element 368 is coupled to the firstcatheter 360 and the second occlusion element 378 is coupled to thesecond catheter 370.

In this embodiment, the occlusion elements 368 and 378 are filterelements that can be moved between a collapsed configuration (alsoreferred to as “retracted configuration” or “closed configuration”) forinsertion of the catheter device 300 into a body of a patient (e.g.,into an artery) and an expanded configuration (also referred to as“dilated configuration” or “open configuration”), as shown in FIG. 12 ,for occluding a portion of an artery. The occlusion elements 368 and 378when in the collapsed configuration have a smaller outer perimeter (ordiameter) than when in the expanded configuration.

The catheter device 300 includes a distal end portion 312 and a proximalend portion 311. FIG. 13 is a side view of the distal end portion 312 ofthe catheter device 300 and FIGS. 14-19 illustrate cross-sections atvarious locations along the distal end portion 312 of the catheterdevice 300. As shown in FIGS. 14-19 , the first catheter 360 defines afirst lumen 363 and a second lumen 365 that each can extend a length ofthe first catheter 360. The first lumen 363 can be configured to receivea wire deployment device 382 that can be coupled to the filter element368 and configured to move the filter element 368 from its expanded oropen configuration and its collapsed or closed configuration. The secondlumen 365 can be configured to receive a guidewire 380 (shown in FIG. 12).

The second catheter 370 defines a first lumen 373, a second lumen 374,and a third lumen 376. The first lumen 373 is configured to slidablyreceive at least a portion of the first catheter 360 therethrough. Thesecond lumen 374 can be configured to receive a wire deployment device381. The wire deployment device 381 can be coupled to the filter element378 and used to move the filter element 378 between its expanded or openconfiguration and its collapsed or closed configuration. The third lumen376 can terminate and be in fluid communication with an infusionaperture 379 (see, e.g., FIG. 16 ) near a distal end 372 of the secondcatheter 370. The infusion aperture 379 can be used to communicate, forexample, a cell or cells (or other therapeutic or biologic material) toa desired location within a body of a patient.

The first Y-adaptor 328 includes a port 320 and a port 325 as shown inFIG. 12 . The port 320 defines a lumen (not shown) that is in fluidcommunication with the first lumen 363 of the catheter 360. The port 325defines a lumen (not shown) that is in fluid communication with thesecond lumen 365 of the catheter 360, and can be used for introductionof the guidewire 380 into the second lumen 365. The second Y-adapter 343includes three ports 330, 335 and 340, as shown in FIG. 12 . The port330 defines a lumen (not shown) that is in fluid communication with thefirst lumen 373 of the second catheter 370 and can receive the firstcatheter 360 therethrough. The port 335 defines a lumen (not shown) thatis in fluid communication with the second lumen 374 of the secondcatheter 370, and the port 335 defines a lumen (not shown) that is influid communication with the third lumen 376 of the second catheter 370.

The filter elements 368 and 378 can each be shaped as a cone when intheir expanded or open configurations as shown in FIGS. 12 and 13 . Thefilter elements 368 and 378 can each be sized when in their expanded oropen configurations to meet the size of a particular vessel diameter inwhich the catheter device 300 is to be deployed. After infusion of cellsor a therapeutic/biologic material through the catheter device 300, thefilter elements 368 and 378 can be collapsed to a smaller size forremoval of the catheter device 300 from the patient.

In some embodiments, a diameter of the occlusion elements (e.g., 268,278, 368, and 378) when expanded within an artery, such as, for example,the splenic artery 40, can be adjustable to meet anatomical variationsincluding a) individual variability in the size of the splenic artery 40and b) end to end variation as the artery size can taper down betweenthe two ends of the artery. As such, in some embodiments, to allowsuccessful isolation of the area for treatment, the proximal occlusionelement (e.g., the balloon 278 and/or the filter element 378) can besized (e.g., have an outer diameter or outer perimeter) between, forexample, 3-12 mm and the distal occlusion element (e.g., the balloon 268and/or the filter element 368) between, for example, 3-12 mm. Theproximal occlusion element can be larger than the distal occlusionelement, smaller than the distal occlusion element, or the same size asthe distal occlusion element.

Referring now to FIGS. 20-29 , a multi-lumen catheter insertion device400 is illustrated according to an embodiment. The multi-occlusioncatheter insertion device 400 (also referred to herein as “catheterdevice” or “device”) includes a handle 410, an actuator 450, a firstcatheter 460 (also referred to herein as “inner catheter”), and a secondcatheter 470 (also referred to herein as “outer catheter”) and can bemovable between a first configuration and a second configuration. Asdescribed in further detail herein, the device 400 can be grasped by auser (e.g., a doctor, physician, surgeon, technician, etc.) andmanipulated substantially single handedly to insert a portion of thefirst catheter 460 and a portion of the second catheter 470 into abodily lumen of a patient and to move, inflate, deflate, adjust, and/orotherwise reconfigure the portion of the first catheter 460 and theportion of the second catheter 470 within the bodily lumen. For example,the second catheter 470 can be moved relative to the first catheter 460,and vice-versa, to adjust a distance between a first occlusion element468 coupled to a distal end portion of the first catheter 460 and asecond occlusion element 478 coupled to a distal end portion of thesecond catheter 470. The device 400 can be used to isolate a segment ofa bodily lumen within the space or region defined between the firstocclusion element 468 and the second occlusion element 478. Thus, aprocedure can then be performed within the isolated segment such as, forexample, delivering a cell or a therapeutic/biological agent to theisolated segment.

The handle 410 of the device 400 can be any suitable shape, size, orconfiguration. For example, in some embodiments, the handle 410 can havea shape and size that can enhance the ergonomics of the device 400. Morespecifically, the handle 410 has a proximal end portion 411, a distalend portion 412, and a medial portion 413 that can be shaped in such amanner as to be easily gripped by a user (e.g., a doctor, physician,surgeon, technician, etc.). In some embodiments, the handle 410 caninclude a grip section 417 (see, e.g., FIG. 21 ) or the like that canhave, for example, a rough surface finish, detents, protrusions, or thelike that can enhance the ergonomics of the handle 410. In otherembodiments, the grip section can be, for example, an insert, anover-mold, or the like that is formed from a relatively deformablematerial and that can have a relatively high coefficient of friction,thereby enhancing the ergonomics of the handle 410.

The proximal end portion 411 of the handle 410 includes a first port 420and a second port 425 collectively referred to herein as a first set ofports 428). The first port 420 and the second port 425 can be anysuitable size, shape, or configuration. In some embodiments, the firstport 420 and the second port 425 can be coupled together via anysuitable method (e.g., an adhesive, ultrasonic welding, mechanicalfastener, and/or the like). In other embodiments, the first port 420 andthe second port 425 can be monolithically formed.

The first port 420 and the second port 425 can extend from the proximalend portion 411 of the handle 410 such that at least a portion of thefirst port 420 and the second port 425 is accessible, as shown in FIGS.20 and 21 . In some embodiments, the first set of ports 428 can be, forexample, a first Y-adapter, substantially similar to the Y-adapter 228and/or 328. In other embodiments, a first port and a second port can be,for example, substantially parallel in a stacked configuration. In yetother embodiments, a handle can include a first port and a second portthat are substantially coaxial and arranged in a substantiallyconcentric configuration such that at least a portion of the first portis disposed within the second port, or vice versa.

Although not shown in FIGS. 14-29 , the first port 420 and the secondport 425 can be physically and fluidically coupled to an exteriordevice, mechanism, and/or the like as described above, for example, withreference to insertion device 100. For example, the first port 420 andthe second port 425 can each define a lumen (described in more detailbelow) in fluid communication with such a device. The first port 420 andthe second port 425 can each include a Luer-Lok® and/or any otherattachment mechanism that can physically and fluidically couple thefirst port 420 and/or the second port 425 to any suitable device eitherdirectly or indirectly (e.g., by an intervening structure such as aflexible tubing to the like). The first set of ports 428 can bephysically and fluidically coupled to the first catheter 460 such thatwhen an external device is coupled to the handle 410 via the first port420 and/or the second port 425, at least the portion of the firstcatheter 460 is placed in fluid communication with that external devicevia the first port 420 and/or the second port 425. For example, thefirst port 420 can be coupled to a device that can, for example, supplya pressurized fluid (e.g., an inert gas, air, saline, water, and/or anyother suitable fluid in gaseous or liquid form) that can flow throughthe first port 420 to be delivered to a portion of the first catheter460, as described in further detail herein. Furthermore, the second port425 can be coupled to a device that can advance a guidewire or the likethrough the second port 425 and into a portion of the first catheter460, as described in further detail herein. In some embodiments, aguidewire or the like can be manually inserted through the second port425 without the use of an external device.

The distal end portion 412 of the handle 410 includes a third port 430,a fourth port 435, and a fifth port 440 (collectively referred to as asecond set of ports 443). In some embodiments, the second set of ports443 includes the fifth port 440 and only one of the third port 430 andthe second port 435. The second set of ports 443 can be any suitablesize, shape, or configuration as described above with reference to thefirst set of ports 428. For example, the second set of ports 443 can be,for example, monolithically and/or unitarily formed. In someembodiments, the second set of ports 443 can be monolithically formedwith the catheter 470. In some embodiments, the second set of ports 443can be formed with and/or coupled to any suitable structure or componentof the handle 410 such that the second set of ports 443 can be movedrelative to the handle 410 as described in more detail below.

The third port 430, the fourth port 435, and the fifth port 440 can eachinclude a Luer-Lok® and/or any other attachment mechanism that canphysically and fluidically couple the third port 430, the fourth port435, and/or the fifth port 440 to any suitable attachment, device,mechanism, and/or the like. The second set of ports 443 can bephysically and fluidically coupled to the second catheter 470 such thatwhen an external device is coupled to the handle 410 via the third port430, the fourth port 435, and/or the fifth port 440, at least a portionof the second catheter 470 is placed in fluid communication with thatexternal device. For example, in some embodiments, the third port 430and/or the fourth port 435 can be coupled to a device that can supply apressurized fluid (as described above) that can flow through the thirdport 430 and/or the fourth port 435, respectively, to be delivered to aportion of the second catheter 470, as described in further detailherein. In some embodiments, the fifth port 440 is coupled to, forexample, an infusion device that is configured to deliver a biologicalor therapeutic agent and/or other suitable drug formulation to a targettissue via the fifth port 440 and a portion of the second catheter 470.In some embodiments, the fifth port 440 can be coupled to, for example,an irrigation device that can deliver an irrigation fluid to, forexample, an isolated segment of a bodily lumen via the fifth port 440and a portion of the second catheter 470. In some embodiments, the fifthport 440 can be coupled to, for example, the infusion device configuredto deliver the biological agent and/or other suitable drug formulation,as described in further detail herein.

As shown in FIGS. 20-22 , the handle 410 defines a first track 414 and asecond track 416. The first track 414 slidably receives a portion of theactuator 450. More specifically, at least a portion of the actuator 450can extend through the track 414, thereby allowing a user to engage theactuator 450. As such, the track 414 can define a path along which theactuator 450 can be moved between a first position relative to thehandle 410 and a second position relative to the handle 410, asdescribed in further detail herein. In a similar manner, the secondtrack 416 slidably receives a portion of the fifth port 440. In thismanner, the fifth port 440 can extend through the second track 416 to beaccessed by a user. Moreover, the second track 416 can define a pathalong which the fifth port 440 can be moved, as described in furtherdetail herein.

Although the device 400 is particularly shown in FIGS. 20-29 , thearrangement of the first set of ports 428, the second set of ports 443,the first track 414 and the second track 416 can be arranged along asurface of the handle 410 in various orientations. For example, althoughthe first track 414 is shown as being defined by a top surface of thehandle 410 (see, e.g., FIG. 20 ) and the second track 416 as beingdefined by a side surface of the handle 410 (see, e.g., FIG. 21 ), inother embodiments, a first track configured to receive an actuator canbe defined by a side surface of a handle and a second track configuredto receive a fifth port can be defined by a top surface of the handle.Similarly, while the first set of ports 428 and the second set of ports443 are shown extending from the handle 410 in a specific orientation,the first set of ports 428 and/or the second set of ports 443 can beoriented in any suitable manner relative to a surface of the handle 410.

The actuator 450 of the device 400 is operably coupled to the second setof ports 443. For example, in some embodiments, the actuator 450 isincluded in and/or coupled to the handle 410 and arranged relative tothe second set of ports 443 to be operably coupled thereto. In otherembodiments, a handle can be arranged such that at least a portion of anactuator is monolithically formed with at least a portion of a secondset of ports. In some embodiments, an actuator is operably coupled to asecond set of ports via an intervening structure or the like. Forexample, in some embodiments, the second set of ports 443 can be coupledto a shuttle or the like, which in turn, is coupled to an actuator. Theactuator 450 can be any suitable device, mechanism, assembly, etc. thatis movable between the first position relative to the handle 410,associated with the device 400 in the first configuration (FIGS. 20-22), and a second position relative to the handle 410, associated with thedevice 400 in the second configuration (FIG. 29 ).

In some embodiments, the actuator 450 can be a mechanism that can bepushed or pulled to slide within the first track 414 defined by thehandle 410 between its first position and its second position. In someembodiments, the actuator 450 can be arranged to slide relativelysmoothly within the track 414 when moved between its first position andits second position. In other embodiments, the handle 410 and/or theactuator 450 can include a set of ribs, teeth, detents, protrusions,etc. that are sequentially engaged as the actuator 450 is moved betweenits first position relative to the handle 410 and its second positionrelative to the handle 410. In this manner, a user can move the actuator450 a desired distance that can be quantified by the actuator 450 and/orthe handle 410 engaging a particular surface (e.g., a particular rib,tooth, detent, protrusion, etc.). In some embodiments, the handle 410and/or the actuator 450 can be arranged at a predetermined setting thatcan correspond to a predetermined distance (e.g., 2 cm, 3 cm, etc.)between an end portion of the first catheter 460 and an end portion ofthe second catheter 470. In some embodiments, the set of ribs, teeth,detents, protrusions, etc. included in the handle 410 and/or theactuator 450 can be associated with pre-defined settings and/oradjustments.

Although not shown in FIGS. 20-29 , in some embodiments, a handle 410can include a visual indicator such as a measuring scale or the like.For example, in some embodiments, the handle 410 can include indicia(e.g., lines, markings, tic marks, etc.) that represents a gradation ofa length of travel associated with moving the actuator 450 between itsfirst position relative to the handle 410 and its second positionrelative to the handle 410. In some embodiments, the markings canrepresent distances of, for example, a centimeter, half a centimeter, amillimeter, and/or the like. In this manner, a user can view the indiciato determine a desired distance to move that actuator 450 that wouldotherwise be challenging or indeterminate. In some embodiments, thevisual indicator can substantially correspond with the ribs, teeth,detents, protrusions, etc. of the handle 410 and/or actuator 450.

In some embodiments, the actuator 450 can be operably coupled to one ormore energy storage device (e.g., a spring or the like) that canfacilitate the movement of the actuator 450. For example, the actuator450 can include a push button that can rearrange or reconfigure at leasta portion of the actuator 450 to allow a spring to transition from acompressed configuration towards an uncompressed configuration to movethe actuator 450 relative to the handle 410.

With the actuator 450 coupled to or monolithically formed with a portionof the second set of ports 443, the actuator 450 can be operable inmoving the second set of ports 443 between a first position relative tothe handle 410 (e.g., a distal position) and a second position relativeto the handle 410 (e.g., a proximal position). Moreover, with the secondcatheter 470 physically and fluidically coupled to the second set ofports 443 (as described above), the movement of the actuator 450 and thesecond set of ports 443 can move the second catheter 470 between a firstposition relative to the handle 410 and a second position relative tothe handle 410, as described in further detail herein.

The first catheter 460 and the second catheter 470 can be any suitablecatheter device. For example, in some embodiments, the first catheter460 and the second catheter 470 are multi-lumen catheters. The firstcatheter 460 has a proximal end portion 461 (see, e.g., FIGS. 21, 23 and29 ) and a distal end portion 462 (see, e.g., FIGS. 20 and 29 ), anddefines a first lumen 463 and a second lumen 465 (see, e.g., FIGS. 24-28). The proximal end portion 461 of the first catheter 460 is disposedwithin a portion of the handle 410. More specifically, the proximal endportion 461 of the first catheter 460 can be fixedly disposed within theportion of the handle 410 to place the first catheter 460 in fluidcommunication with the first set of ports 428. In some embodiments, thefirst catheter 460 can be physically and fluidically coupled to thefirst set of ports 428. In other embodiments, a device can include afirst catheter that is monolithically formed with a first set of ports.In this manner, the proximal end portion 461 of the first catheter 460is arranged such that the first lumen 463 of the first catheter 460 isin fluid communication with a lumen 421 defined by the first port 420and the second lumen 465 of the first catheter 460 is in fluidcommunication with a lumen 426 of the second port 425, as shown in FIG.23 . Therefore, an external device (e.g., a device that can supply apressurized fluid, as described above) can be physically and fluidicallycoupled to the first port 420 to place the external device in fluidcommunication with the first lumen 463 of the first catheter 460.Similarly, an external device including at least a guidewire (not shown)can be coupled to the second port 425 and can be manipulated to advancethe guidewire through the second port 425 and into the second lumen 465,as described in further detail herein.

Referring back to FIG. 20 , the distal end portion 462 of the firstcatheter 460 extends beyond a distal end portion of the handle 410 andincludes an occlusion member 468. The occlusion member 468 can be anysuitable device or mechanism that is configured to selectively limit,block, obstruct, or otherwise occlude a body lumen (e.g., artery) inwhich the occlusion member 468 is disposed. For example, in someembodiments, the occlusion member 468 can be an inflatable balloon orthe like that can be transitioned between a collapsed (e.g., deflated)configuration and an expanded (e.g., inflated) configuration.

The arrangement of the first catheter 460 can be such that the firstlumen 463 is in fluid communication with the occlusion member 468. Forexample, as shown in FIG. 24 , the distal end portion 462 of the firstcatheter 460 can define a channel 464 that places the first lumen 463 influid communication with the occlusion member 468. Thus, when the firstport 420 is fluidically coupled to a device that supplies a pressurizedfluid (e.g., air, inert gas, or liquid), the pressurized fluid can bedelivered to the occlusion member 468 via the lumen 421 of the firstport 420, the first lumen 463 of the first catheter 460, and the channel464 of the first catheter 460. In this manner, the pressurized fluid cantransition the occlusion member 468 between a collapsed configuration(not shown) and an expanded configuration (see e.g., FIG. 20 ), asdescribed in further detail herein.

The second catheter 470 of the device 400 has a proximal end portion 471(see, e.g., FIGS. 20-22 ) and a distal end portion 472 (see, e.g., FIGS.20 and 29 ), and defines a first lumen 473, a second lumen 474, a thirdlumen 476 and an opening 479 (also referred to herein as “infusionaperture”) (as shown, for example, in FIGS. 25-28 ). The second catheter470 is movably disposed about a portion of the first catheter 460 (see,e.g., FIGS. 21-23 ). More specifically, the second catheter 470 can bearranged such that the first catheter 460 is movably disposed within thefirst lumen 473 defined by the second catheter 470, as shown, forexample, in FIGS. 26-28 .

The proximal end portion 471 of the second catheter 470 is movablydisposed within the handle 410 to place the second catheter 470 in fluidcommunication with the second set of ports 443. In some embodiments, thesecond catheter 470 can be physically and fluidically coupled to thethird port 430 and the fourth port 435, and/or the fifth port 440. Inother embodiments, a catheter insertion device can include a secondcatheter that can be movably disposed within a handle and can beoperably coupled to one or more ports via an intervening structure suchas, for example, flexible tubing or the like. In yet other embodiments,a catheter insertion device can include a second catheter that ismonolithically formed with a third port, a fourth port, and/or a fifthport. In this manner, the second catheter 470 is arranged such that thefirst lumen 473 of the second catheter 470 movably receives the firstcatheter 460, the second lumen 474 of the second catheter 470 is influid communication with a lumen 431 defined by the third port 430 and alumen 436 defined by the fourth port 435, and the third lumen 476 of thesecond catheter 470 is in fluid communication with a lumen 441 definedby the fifth port 440, as shown in FIG. 25 .

Referring back to FIG. 20 , the distal end portion 472 of the firstcatheter 470 extends beyond a distal end portion of the handle 410 suchthat an occlusion member 478 of the second catheter 470 is disposed in aproximal position relative to the occlusion member 468 of the firstcatheter 478. Expanding further, the first catheter 460 extends withinthe proximal end portion 471 and the distal end portion 472 whendisposed in the first lumen 473. Thus, the occlusion member 468 of thefirst catheter 460 can be disposed in a distal position relative to theocclusion member 478 of the second catheter 470. The occlusion member478 can be any suitable device or mechanism that is configured toselectively limit, block, obstruct, or otherwise occlude a body lumen(e.g., artery) in which the occlusion member 478 is disposed. Forexample, in some embodiments, the occlusion member 478 can besubstantially similar to the occlusion member 468 of the first catheter468.

The arrangement of the second catheter 470 can be such that the secondlumen 474 is in fluid communication with the occlusion member 468. Forexample, as shown in FIG. 27 , the distal end portion 472 of the secondcatheter 470 defines a channel 475 that places the second lumen 474 influid communication with the occlusion member 478. Thus, when the thirdport 430 (and/or the fourth port 435) is fluidically coupled to a devicethat supplies a pressurized fluid, the pressurized fluid can bedelivered to the occlusion member 478 via the lumen 431 of the thirdport 430 (and/or the lumen 436 of the fourth port 435), the second lumen474 of the second catheter 470, and the channel 475 of the secondcatheter 470. In this manner, the pressurized fluid can transition theocclusion member 478 between a collapsed configuration (not shown) andan expanded configuration (as shown in FIGS. 20 and 29 ). In a similarmanner, the arrangement of the second catheter 470 can be such that thethird lumen 476 is in fluid communication with the opening 479 (see,e.g., FIG. 28 ). For example, the distal end portion 472 of the secondcatheter 470 defines a channel 477 that places the third lumen 476 influid communication with the opening 479, as shown in FIG. 28 . Thus,when the fifth port 440 is fluidically coupled to an external devicethat supplies irrigation or to a device that supplies a therapeuticagent, the irrigation fluid or therapeutic agent can be delivered to anisolated segment of a bodily lumen via the lumen 441 defined by thefifth port 440 and the third lumen 476, the channel 477, and the opening479 defined by the second catheter 470.

The device 400 can be moved from the first configuration to the secondconfiguration by moving the actuator 450 from its first position (e.g.,a distal position) relative to the handle 410 to its second position(e.g., a proximal position) relative to the handle 410, as indicated bythe arrow BB in FIG. 29 . Expanding further, with the second catheter470 movably disposed about the first catheter 460 and with the proximalend portion 471 of the second catheter 470 operably coupled to theactuator 450, the movement of the actuator 450 from its first positionto its second position moves the second catheter 470 relative to thefirst catheter 460, as indicated by the arrow CC in FIG. 29 . Forexample, when the device 400 is in the first configuration, a firstdistance D7 (FIG. 20 ) can be defined between the occlusion member 468of the first catheter 460 and the occlusion member 478 of the secondcatheter 470. With the first catheter 460 fixedly disposed within thehandle 410, the movement of the second catheter 470 in the CC direction(e.g., the proximal direction) increases the distance between theocclusion member 468 of the first catheter 460 and the occlusion member478 of the second catheter 470 to a second distance D8, as shown in FIG.29 . Thus, a segment or volume having a desired length can be definedbetween the occlusion member 468 of the first catheter 460 and theocclusion member 478 of the second catheter 470.

In use, a guidewire can be inserted into the lumen 426 of the secondport 425 and through the second lumen 465 defined by the first catheter460. In this manner, the guidewire can be advanced through a bodilylumen and the device 400 can be manipulated to advance the firstcatheter 460 and the second catheter 470 along the guidewire. Thus, thedistal end portion 462 of the first catheter 460 and the distal endportion 472 of the second catheter 470 can be placed at a targetlocation within the bodily lumen such as, for example, the haptic orsplenic artery of the pancreas, as shown in FIG. 30 . At the targetlocation, the actuator 450 can be moved between its first position andits second position relative to the handle 410 (e.g., the BB directionin FIG. 29 ) to define a desired distance (e.g., the distance D8 in FIG.29 ) between the occlusion member 468 of the first catheter 460 and theocclusion member 478 of the second catheter 470. With the desireddistance defined between the occlusion members 468 and 478, and with aninflation source coupled to the first port 420 and the same or adifferent inflation source coupled to the third port 430 (and/or thefourth port 435), the occlusion member 468 of the first catheter 460 andthe occlusion member 478 of the second catheter 470, respectively, canbe transitioned from a collapsed or deflated configuration to anexpanded or inflated configuration to substantially isolate a segment ofthe bodily lumen disposed therebetween (e.g., the pancreatic segment orportion of the splenic artery 40 associated with, for example, thedorsal pancreatic artery 42 and/or the pancreatic magnum artery 44), asshown in FIG. 30 . FIG. 30 is an illustration of the catheter device 400disposed in situ within the splenic branch of the celiac artery. Asshown in FIG. 30 , the occlusion elements 468 and 478 define or isolatean area of interest in between the occlusion elements 468 and 478.Specifically, in this example, the region or area of interest with bloodsupply to the pancreas is isolated via the occlusion elements 468 and478, spaced according to the location of the dorsal pancreatic artery 42and the pancreatic magnum artery 44.

With the occlusion members 468 and 478 substantially occluding the bodylumen, a biological/therapeutic agent can be delivered to thesubstantially isolated segment via the fifth port 440, the third lumen476, and the opening 479 (i.e., the infusion aperture), into the areasubstantially isolated between the occlusion elements 468 and 478. Insome instances, the substantially isolated segment can be irrigated bycoupling an irrigation source to the fifth port 440. Thus, theirrigation can be delivered to the substantially isolated segment viathe lumen 441 of the fifth port 440 and the third lumen 476, the channel477, and the opening 479 of the second catheter 470. In some instances,such irrigation can be delivered prior to the delivery of thebiological/therapeutic agent, after the delivery of thebiological/therapeutic agent, or substantially concurrently with thebiological/therapeutic agent.

FIG. 31 is a flowchart illustrating a method of accessing and treating apancreas. The method can be used, for example, to occlude a portion ofthe splenic branch of the celiac artery supplying the pancreatic tail.The method includes introducing a catheter (e.g., the catheter device100, 200, 300, and/or 400) into a mammalian body over a guidewire (211,311) into a celiac artery, at 501. The catheter device can include aninner catheter (e.g., the first catheter 160, 260, 360, and/or 460)slidably coupled to an outer catheter (e.g., the second catheter 170,270, 370, and/or 470). In some embodiments, a guide catheter can beexchanged over the guidewire into the celiac artery for support andintroduction of the catheter device. After the guidewire is in place,the catheter device can be positioned over the guidewire, at 502, andpositioned to allow placement of a distal occlusion element (e.g., thedistal occlusion element 168, 268, 368, and/or 468) of the innercatheter at a distal edge of the pancreatic portion of the splenicartery (see, e.g., FIG. 30 ). The distal occlusion element and aproximal occlusion element (e.g., the proximal occlusion element 178,278, 378, and/or 478) of the outer catheter are positioned to isolate atarget portion of the pancreatic artery and moved to an expandedconfiguration, at 503. After the occlusion elements are deployed,contrast dye is injected through an injection port of the outer catheterand the isolated area of the splenic artery is visualized to identifythe pancreatic branches, at 504. Visualization enables the clinician toconfirm isolation of the pancreatic magnum artery and dorsal pancreaticartery or any other large artery supplying the pancreatic body or tailin the area, at 505. If desired, the catheter device can be moved backand the procedure repeated until the clinician can confirm that thecatheter is correctly positioned. Some example isolation regionsinclude: (a) the pancreatic magnum artery 44 (and its branches), (b) thedorsal pancreatic artery 42 if the origin is within the splenic artery40, and (c) both pancreatic magnum artery 44 and dorsal pancreaticartery 42 arteries are isolated in one contiguous area (if otherextra-pancreatic arteries do not arise between the origin of the twowithin the splenic artery 40).

After the first takeoff of the pancreatic magnum artery 44 is identified(or the dorsal pancreatic artery), the placement of the outer catheterof the catheter device can allow the edge of the distal occlusionelement to be placed beyond this artery. At this point, the innercatheter can be secured in place, and the outer catheter can be movedrelative to the inner catheter to allow the maximum perfusion area tothe body and tail of the pancreas. Frequent injection of contrastthrough the infusion port can be made to ensure no extra-pancreaticvessels are included in the isolated area.

After the desired area is isolated and the occlusion elements arepositioned at a desired location, the therapeutic cells/biologics/agentis introduced to the isolated area of the splenic artery through theinfusion port of the outer catheter, at 506. The infusion port designcan allow rapid and atraumatic infusion of cells/biologics/agent intothe isolated area. This allows the clinician to adjust rate of infusionof therapeutic cells/biologics/agents into the isolated area based onspecific pharmacodynamics and or engraftment efficiency requirements.The infusion of the therapeutic material can be followed by heparinizedblood to exclude any residual cells left behind in the dead space of thecatheter device. During isolation of the artery described above,perfusion to the end organ to the artery spleen can be disrupted, butthe redundancy in the arterial perfusion system to the spleen, andlimited time during which the arterial supply is interrupted, shouldprevent any long-term sequela, or abnormal condition of the spleniccells. If needed and/or desired, the guidewire port can be used toperform perfusion of the splenic artery beyond the isolated area. Forexample, the guidewire can be removed from its port after the catheterdevice is in place, and the guidewire port can be connected to a sourceof arterial blood with suitable pressure (i.e. the side port of anarterial sheath or guide sheath). At the end of the infusion, bothocclusion elements are moved to a collapsed configuration and thecatheter device is removed from the body over the guidewire as one unit,followed by the guidewire and the guide catheter.

In a variation of the method described above using balloons as theocclusion elements, the same catheter can be used to isolate arterialbranches supplying the head of the pancreas via the hepatic artery orsuperior mesenteric artery. One such clinical possibility is treatmentof pancreatic cancer with the tumor located in the head of the pancreas.After placement of the catheter device in the respective artery, theinfusion of contrast through the infusion port can identify the branchesmost proximate to the tumor, and then after occluding the distal andproximal portion of the artery around the branch(es), thechemotherapeutic agent can be delivered selectively to the area ofinterest in the pancreas.

In some embodiments, a method can include introducing a catheter deviceinto a splenic artery. The catheter device can include an innercatheter, a first expandable occlusion element coupled to the innercatheter, an outer catheter defining a first lumen configured tointroduce a therapeutic biologic/agent to one or more target pancreaticvessels, a second lumen configured to slidably receive at least aportion of the inner catheter, and a second expandable occlusion elementcoupled to the outer catheter and disposed proximally to the firstocclusion element. The catheter is advanced to a target pancreaticportion of the splenic artery. A region of the target pancreatic portionof the splenic artery is selectively isolated and the therapeuticbiologic/agent is injected into the isolated region. In someembodiments, the therapeutic biologic/agent includes stem cells. In someembodiments, the method further includes advancing at least a portion ofthe catheter device to an ostium of a celiac artery, its hepatic branch,or if necessary, the superior mesenteric artery (based on individualanatomy). In some embodiments, a contrast dye is injected into theisolated region and isolation of a pancreatic magnum artery and/or adorsal pancreatic artery can be confirmed. In some embodiments, aguidewire can be disposed through the infusion lumen to focallyperforate the vascular lumen in the isolated area to increase exogenouscell penetration into the pancreatic tissue. In some embodiments, thetherapeutic biologic can be introduced into the isolated segment orregion to enhance cellular transmigration across the endothelial cellsprior to introduction of the therapeutic biologic.

In some embodiments, a method can include introducing a catheter deviceinto a bile duct. In use, the catheter device 200 can be placed at adesired location within the bile duct and used to infuse a therapeuticagents into the bile duct which will diffuse through the bile duct intothe pancreas. A length of the first catheter 260 and the second catheter270 can be adjusted such that a selected portion of the bile duct isisolated between the first occlusion element 268 and the secondocclusion element 278. A therapeutic agent can be injected through thecatheter device 200 and into the isolated region of the bile duct.

The infusion pressure in the isolated blood vessel region can bemeasured with pressure monitoring through the infusion lumen of thecatheter (with a monometer (not shown) in line with infusion port 279).The pressure in the third lumen 276 can be based on the size of theagents being delivered, on the flow rate, the viscosity of the solution,and/or flow resistance of the third lumen 276 of second catheter 270.The flow resistance of the catheter device 200 can in turn be determinedbased on, for example, the inner coating material, the size and thelength of the third lumen 276, the size of the third port 240, and/orthe size of the distal infusion aperture 279. The catheter device 200can allow for rapid infusion of agents (e.g., up to 2 milliliter persecond (ml/sec)). In some applications, the rapid infusion can enhanceuptake and eventual engraftment.

Any catheter device described herein and/or any combination of thecatheter devices described herein can allow the above goals to beachieved. For example, a catheter device can include two cathetersslidably coupled where an inner catheter defines a guidewire housingport and a distal occlusion element, and an outer catheter forms aninfusion port and a proximal occlusion element, along with an innerlumen allowing the insertion of the inner catheter. The two catheterscan be assembled outside the body with a distance between the twoocclusion elements set to a desired length. For example, in someembodiments, the minimum distance between the two occlusion elements canbe 3 cm, and the length can be adjusted up to a distance between the twoocclusion elements of 25 cm as needed.

The devices described herein can also be provided in a kit. In someembodiments, a kit for use in the delivery of a biological agent to anarea proximal to the pancreas can include, for example, one or morecatheter devices (e.g., the catheter devices 100, 200, 300, and/or 400)as described herein and one or more biologic/therapeutic agent fordelivery to the pancreas. The catheter devices can include, for example,a proximal end portion, a distal end portion and one or more expandabledevices, such as a balloon or a filter, associated therewith. In someembodiments, the catheter device can include a first catheter configuredto be slidably received within a lumen of a second catheter, a firstocclusion element coupled to the first catheter and a second occlusionelement coupled to the second catheter. In such an embodiment, adistance between the first and second occlusion elements can be variedor adjusted. The occlusion elements can be expandable to engage a wallof a blood vessel thereby substantially isolating an interior region ofthe vessel between the first and second occlusion elements. Moreover,the first and second catheters can be configured such that at least oneof the first and second catheters has a lumen configured to deliver abiological/therapeutic agent to the isolated interior region via aninfusion port. The infusion port can allow for rapid and atraumaticdelivery of cells/biologics into the isolated area. In some embodiments,a pressure regulator can be provided that is configured to regulate thefluid pressure of the agent or the materials used to dilate theocclusion element(s) (e.g., in a balloon embodiment).

In some embodiments, a kit can further include one or morebiologic/therapeutic agents for delivery to the pancreas, a stylet(s);one or more catheters adapted and configured for accessing thepancreatic vessels; a dilator; a guidewire; a guide catheter; capsulesfor direct connection of biological materials/cells to the infusion portof the delivery catheter; a manometer to monitor the pressure in theisolated area; and/or a pump to regulate the infusion rate ofcells/biologics.

In some embodiments, any of the components of a kit can be packagedtogether and collectively sold as a catheter device or can be packagedindependently or in subgroups and sold together or separately. Forexample, in some embodiments, the handle 410 can be packagedindependently from the first catheter 460 and the second catheter 470.Moreover, the first catheter 460 and the second catheter 470 can bepackaged independent from one another or packaged together. As such, thehandle 410 can be sold independent of the first catheter 460 and thesecond catheter 470. The first catheter 460 and the second catheter 470can be sold independent of one another or together. Thus, in someembodiments, the handle 410 can be packaged independent of the firstcatheter 460 and the second catheter 470 and, prior to use, can becoupled to the first catheter 460 and the second catheter 470 such thatthe first set of ports 428 are in fluid communication with thecorresponding lumen of the first catheter 460 and the second set ofports 443 are in fluid communication with the corresponding lumen of thesecond catheter 470. In some embodiments, the handle 410 can be, forexample, reusable, while the first catheter 460 and the second catheter470 are disposable. In other embodiments, the handle 410 can be coupledto the first catheter 460 and the second catheter 470 during, forexample, a manufacturing process and packaged together to be sold as acomplete catheter device.

In some embodiments, placement of the occlusion elements (e.g., thedistal occlusion elements 168, 268, 368, and/or 468 and the proximalocclusion elements 178, 278, 378, and/or 478) and the lengths of eachregion therebetween can be varied based on the needs of the individualapplication. The catheter devices 100, 200, 300 and/or 400 can retainsufficient trackability to allow advancement into the target region ofthe patient. In some embodiments, the catheter material can be flexibleenough to traverse local anatomy yet have enough tensile strength to beable to be placed in position in place over a guidewire (e.g., theguidewire 280 and/or 380). Furthermore, for the first catheters 160,260, 360, and 460 and the second catheters 170, 270, 370, and 470,respectively, to be slidable relative to each other in situ, variousradial and tensile strengths can be incorporated in each.

The first catheters 160, 260, 360, and/or 460 (i.e., the innercatheters) and the second catheters 170, 270, 370, and/or 470 (i.e., theouter catheters) can be fabricated of any material suitable forcatheters, such as linear low density or high density polyethylene,nylon, polyurethane, polypropylene, silicone rubber, or othernon-thrombogenic materials. In some embodiments, an outer catheter canbe formed from a linear low-density polyethylene, while an innercatheter can be formed from a nylon. In some embodiments, the outercatheters described herein can be fabricated to include a structure forreinforcement (not shown), such as a metal braid or the like locatedbetween an inner and outer layer. The reinforcement structure can extendalong any desired length of such outer catheters. In some embodiments, areinforcement structure can extend along the entire length of an outercatheter.

In some embodiments, regions of a first catheter (i.e., an innercatheter) such as those described herein can also be fabricated in anymanner that allows the relative stiffness of each region to vary. Insome embodiments, an outer layer in each region of an outer catheterand/or an inner catheter can include a material with a differentdurometer measurement of hardness. For example, the material used in anintermediate region can be relatively harder than that used in a distalregion, and the material used in a proximal region can be relativelyharder than that used in the intermediate region. Other manners ofvarying the stiffness of an inner catheter and/or an outer catheter(i.e., a first catheter and a second catheter, respectively, such asthose described herein) can include varying the length of areinforcement structure, varying the degree of reinforcement provided bythe reinforcement structure along the length of the inner catheterand/or the outer catheter, changing a cross-sectional size and/or shapeof the inner catheter and/or the outer catheter, introducing and/orforming one or more discontinuities along a length of the inner catheterand/or the outer catheter (e.g., one or more ribs, notches, grooves,protrusions, etc.), and/or any other suitable means for varyingstiffness.

In some embodiments, the catheter devices described herein can includeone or more sensors that can provide relative information such as, forexample, position of the occlusion members, movement of the actuator,flow rate of the biological agent, and/or any other suitableinformation. For example, in some embodiments, a sensor can be operablycoupled to the actuator 450 of the device 400 and can be configured toprovide information associated with a distance that the actuator 450 hasbeen moved. In such embodiments, a user and/or an electronic device candetermine a distance between the occlusion member 468 of the firstcatheter 460 and the occlusion member 478 of the second catheter 470based on the information from the sensor. In some embodiments, a sensorcan be disposed within the third lumen 476 of the second catheter 470that can be configured to determine a flow rate of irrigation and/or abiological/therapeutic agent therethrough.

In some embodiments, radiopaque markers of gold or tantalum, forexample, can also be provided on or in an inner catheter positioned,within or on an occlusion element(s) (e.g., the occlusion elements 168,178, 268, 278, 368, 378, 468, and/or 478), and/or on an outer catheterto aid in visualization and to assist in monitoring the position of atleast a portion of a catheter device (e.g., the catheter devices 100,200, 300, and/or 400) on an imaging device (e.g., a fluoroscope, anX-Ray, a Magnetic Resonance Imaging (MRI) scan, a computerizedtomography (CT) scan, and/or the like) during a procedure. In someembodiments, an inner catheter can optionally be coated with a lubricousmaterial, such as silicone, acrylamide, or a hydrophilic polyurethanecoating, to ease retraction. Similarly, the outer catheter and theocclusion elements can be coated with the lubricous material to easeadvancement through a guiding catheter and/or a tortuous vessel.

In some embodiments, an outer diameter of an outer catheter (e.g., thesecond catheters 100, 200, 300 and/or 400) and non-deployed occlusionelements (e.g., the occlusion elements 168 and 178, 268 and 278, 368 and378, and/or 468 and 478) can be, for example, between about 6 French andabout 8 French and thus, can be used with, for example, a 7-9 Frenchguiding catheter (if need be).

In some embodiments, after a guidewire (e.g., the guidewire 280 and/or380) is removed, a corresponding lumen (e.g., the first lumen 265, 365,and/or 465 of the first catheter 160, 260, 360, and/or 460,respectively) can be used to establish arterial blood flow distal to theocclusion end (e.g., the distal end portion) of a catheter device orinfusion of other therapeutic agents if desired.

In some embodiments, any suitable configuration of the catheter devicescan be used to achieve the objectives described herein including, forexample, employing one or more catheter devices 100, 200, 300, and/or400, employing a contiguous inflation/occluding section having differingstiffness along its length to achieve the two occluding elements, and/orthe like.

In some embodiments, to allow endovascular isolation of the pancreaticportion of the splenic artery 40 (see e.g., FIG. 1 ) as a mechanism toachieve substantially exclusive delivery of a therapeutic agent/cells tothe pancreatic parenchyma, a catheter device such as those describedherein can include anatomical and mechanical features such as, forexample, isolation of the two ends of the pancreatic portion of theartery using two occlusion elements; adjustment of the diameter of theocclusion elements to meet the specific anatomical needs; adjustment ofthe distance between the two occlusion elements (based on individualvariation to selectively isolate for instance the portion of the splenicartery 40 to the pancreas 30 on one hand and maximize the perfusion areaon the other hand); an infusion port where injection of contrast can beused to visualize the area of the artery isolated; an infusion port,shaft, and/or aperture design to allow atraumatic and rapid delivery ofcells/therapeutic agents; and/or recovery of the occlusion element alongwith the catheter at the end of the procedure, prior to which flushesthrough the infusion port can assure clearance of the cells from theisolated space.

In some instances, any portion of the catheter devices 100, 200, 300,and/or 400 can be rotated to allow for a more targeted delivery of thebiological/therapeutic agent to a selected tissue. For example, whilethe infusion apertures 279, 379 and 479 are shown as being disposed at aspecific position relative to the pancreas 30, in some instances, thecatheter device 100, 200, 300, and/or 400 can be rotated to rotate thesecond catheter 470 relative to the pancreas 30. Thus, the infusionaperture 279, 379, and/or 479 is rotated about a longitudinal axis (notshown) defined by the second catheter 270, 370, and/or 470. As such, theinfusion aperture 279, 379, and/or 479 can be positioned adjacent to atarget tissue for a more accurate delivery of the biological agent thanwould otherwise be possible. In some embodiments, any portion of thecatheter device 200, 300, and/or 400 can include indicia and/or markingsthat can be associated with the relative position of the infusionaperture 279, 379, and/or 479. In this manner, a user can visualize theradial position of, for example, an actuator (e.g., the actuator 450) todetermine the radial position of the infusion aperture 279, 379, and/or479.

Any catheter device described herein and/or any combination of thecatheter devices described herein can allow the above goals to beachieved. For example, a catheter device can include two cathetersslidably coupled where an inner catheter defines a guidewire housingport and a distal occlusion element, and an outer catheter forms aninfusion port and a proximal occlusion element, along with an innerlumen allowing the insertion of the inner catheter. The two catheterscan be assembled outside the body with a distance between the twoocclusion elements set to a desired length. For example, in someembodiments, the minimum distance between the two occlusion elements canbe 3 cm, and the length can be adjusted up to a distance between the twoocclusion elements of 25 cm as needed.

In some embodiments, a catheter device such as those described herein,which is suitable for accessing the pancreas 30 (see e.g., FIG. 1 ) caninclude features and/or functions, such as, for example, selectiveisolation of the targeted portion of the pancreatic portion of thesplenic artery 40 for targeted delivery of the therapeutic agent to thepancreas 30; an adjustable distance between the two ends of theperfusion/infusion area (e.g., an isolated region) to accommodateindividual anatomy to allow isolation of the largest portion of thesplenic artery 40 with branches only supplying the pancreatic tail 32and body 34 (see e.g., FIG. 1 ) and if clinically indicated, the samecatheter can be used to isolate portions of the hepatic artery 54 and/orsuperior mesenteric artery 52 supplying the head of the pancreas 38; aninfusion port allowing first, injection of contrast into the isolatedsegment to allow direct visualization of the origin of the branches ofthe splenic artery 40 supplying the pancreatic tissue, and second,introduction of therapeutic drugs/cells, the dimensions and design ofthe infusion port and catheter shaft allowing rapid and atraumaticdelivery of cells; adjustable diameter of the proximal and/or distaloccluders to allow both intravariable and intervariable sizes of thesplenic artery 40; and/or a self-contained assembly unit with easyretrieval after completion of the procedure.

While various embodiments have been described above, it should beunderstood that they have been presented by way of example only, and notlimitation. Where schematics and/or embodiments described above indicatecertain components arranged in certain orientations or positions, thearrangement of components may be modified. While the embodiments havebeen particularly shown and described, it will be understood thatvarious changes in form and details may be made. Although variousembodiments have been described as having particular features and/orcombinations of components, other embodiments are possible having acombination of any features and/or components from any of embodiments asdiscussed above. For example, the size and specific shape of the variouscomponents can be different from the embodiments shown, while stillproviding the functions as described herein. Furthermore, each featuredisclosed herein may be replaced by alternative features serving thesame, equivalent or similar purpose, unless expressly stated otherwise.Thus, unless expressly stated otherwise, each feature disclosed is oneexample only of a generic series of equivalent or similar features.

For example, although the outer catheters 170, 270, 370, and/or 470 ofthe catheter devices 100, 200, 300, and/or 400 include an infusion lumen(i.e., a third lumen) and infusion port and/or aperture to deliver acell/biologic/therapeutic material to a desired blood vessel, in otherembodiments, the inner catheter 160, 260, 360, and/or 460, respectively,can include the infusion lumen. Similarly, although the guidewire lumen(i.e., a second lumen) is described as being defined by the innercatheter 160, 260, 360, and/or 460, a guidewire lumen can bealternatively, or in addition to, included in and/or defined by theouter catheter 170, 270, 370, and/or 470. Thus, any of the lumens of thecatheter devices 100, 200, 300, and/or 400 can be defined by either thefirst catheter 160, 260, 360, and/or 460 (i.e., an inner catheter) orthe second catheter 170, 270, 370, and/or 470 (i.e., an outer catheter).In another example, although shown coupled to the second catheter 270and/or 370, the sealing element 285 and/or 385 can alternatively becoupled to the first catheter 260 and/or 360.

Although the catheter devices 100, 200, 300, and/or 400 have been shownand described as having either two balloon occlusion elements or twofilter elements, in alternative embodiments, a catheter device caninclude a combination of occlusion elements. For example, a catheterdevice such as those described herein can include one or more balloonocclusion elements (e.g., the balloon elements 268 and/or 278) and oneor more filter element occlusion elements (e.g., the filter elements 368and/or 378).

While various embodiments have been described above, it should beunderstood that they have been presented by way of example only, and notlimitation. Where schematics and/or embodiments described above indicatecertain components arranged in certain orientations or positions, thearrangement of components may be modified. While the embodiments havebeen particularly shown and described, it will be understood thatvarious changes in form and details may be made. Although variousembodiments have been described as having particular features and/orcombinations of components, other embodiments are possible having acombination of any features and/or components from any of embodiments asdiscussed above. For example, the size and specific shape of the variouscomponents can be different from the embodiments shown, while stillproviding the functions as described herein. Furthermore, each featuredisclosed herein may be replaced by alternative features serving thesame, equivalent or similar purpose, unless expressly stated otherwise.Thus, unless expressly stated otherwise, each feature disclosed is oneexample only of a generic series of equivalent or similar features.

Where methods and/or events described above indicate certain eventsand/or procedures occurring in certain order, the ordering of certainevents and/or procedures may be modified. Additionally, certain eventsand/or procedures may be performed concurrently in a parallel processwhen possible, as well as performed sequentially as described above.

What is claimed is:
 1. A method of treatment, the method comprising:inserting a catheter into a bile duct including a cholangiocarcinoma;occluding the bile duct with a first occluder on a distal end region ofthe catheter and a second occluder on the distal end region of thecatheter proximal to the first occluder, to isolate a region of the bileduct including the cholangiocarcinoma; passing a guidewire through alumen of the catheter to focally perforating a tissue within theisolated region before delivering a therapeutic agent; delivering thetherapeutic agent into the isolated region of the bile duct includingthe cholangiocarcinoma; and maintaining a pressure in the isolatedregion of the bile duct to diffuse the therapeutic agent into thecholangiocarcinoma within the bile duct.
 2. The method of claim 1,further comprising placing a stent to open the bile duct prior todelivering the therapeutic agent.
 3. The method of claim 1, whereinmaintaining the pressure of the isolated region of the bile ductcomprises delivering the therapeutic agent into the isolated region ofthe bile duct under pressure.
 4. The method of claim 1, furthercomprising increasing or decreasing the pressure in the isolated regionof the bile duct to change a penetration depth of the therapeutic agentinto the cholangiocarcinoma within the bile duct.
 5. The method of claim1, wherein inserting the catheter comprises advancing the catheter overthe guidewire within the bile duct.
 6. The method of claim 1, whereininserting the catheter comprises inserting the catheter into the bileduct to a region of the bile duct that includes the cholangiocarcinoma.7. The method of claim 1, wherein inserting the catheter comprisesinserting the catheter through an endoscopic retrogradecholangiopancreatogram (ERCP) catheter.
 8. The method of claim 1,wherein inserting the catheter comprises inserting the catheterpercutaneously.
 9. The method of claim 1, wherein inserting the cathetercomprises adjusting a distance between the first occluder and the secondoccluder by advancing the first occluder distally, wherein the firstoccluder is on an inner catheter slidably disposed within a lumen of thecatheter.
 10. The method of claim 1, wherein occluding the bile ductcomprises inflating the first occluder and the second occluder.
 11. Themethod of claim 1, wherein the therapeutic agent is selected from agroup of: 5-fluorouracil (5-FU), Aldesleukin, Axitinib, Bleomycin,Carboplatin, Cetuximab, Cisplatin, Cyclophosphamide, Dacarbazine,Doxorubicin Hydrochloride, doxorubicin liposomal non-pegylated(un-coated), doxorubicin liposomal pegylated (PEG coated), Floxuridine,Gemcitabine Hydrochloride, Irinotecan Hydrochloride Liposome, LanreotideAcetate, leucovorin (antidote to folic acid antagonist used with 5FU),Methotrexate, Mitomycin, Mitoxantrone, Nivolumab, Olaparib, Oxaliplatin,Sorafenib Tosylate, Temsirolimus, Thiotepa, Topotecan Hydrochloride,Vinblastine Sulfate, vincristine sulfate.
 12. A method of treatment, themethod comprising: inserting a catheter into a bile duct to a region ofthe bile duct including a cholangiocarcinoma; isolating the region ofthe bile duct including the cholangiocarcinoma by occluding the bileduct with a first occluder on a distal end region of the catheter and asecond occluder on the distal end region of the catheter proximal to thefirst occluder; passing a guidewire through a lumen of the catheter tofocally perforating a tissue within the isolated region beforedelivering a therapeutic agent; delivering the therapeutic agent intothe isolated region of the bile duct from out of an opening in a sidewall of the catheter between the first occluder and the second occluder;and diffusing the therapeutic agent into the cholangiocarcinoma bymaintaining the pressure in the isolated region of the bile duct. 13.The method of claim 12, further comprising increasing or decreasing thepressure in the isolated region of the bile duct to change a penetrationdepth of the therapeutic agent into the cholangiocarcinoma.
 14. Themethod of claim 12, wherein inserting the catheter comprises advancingthe catheter over the guidewire within the bile duct.
 15. The method ofclaim 12, wherein inserting the catheter comprises inserting thecatheter through an endoscopic retrograde cholangiopancreatogram (ERCP)catheter.
 16. The method of claim 12, wherein inserting the cathetercomprises adjusting a distance between the first occluder and the secondoccluder by advancing the first occluder distally, wherein the firstoccluder is on an inner catheter slidably disposed within a lumen of thecatheter.
 17. The method of claim 12, wherein the therapeutic agent isselected from a group of: 5-fluorouracil (5-FU), Aldesleukin, Axitinib,Bleomycin, Carboplatin, Cetuximab, Cisplatin, Cyclophosphamide,Dacarbazine, Doxorubicin Hydrochloride, doxorubicin liposomalnon-pegylated (un-coated), doxorubicin liposomal pegylated (PEG coated),Floxuridine, Gemcitabine Hydrochloride, Irinotecan HydrochlorideLiposome, Lanreotide Acetate, leucovorin (antidote to folic acidantagonist used with 5FU), Methotrexate, Mitomycin, Mitoxantrone,Nivolumab, Olaparib, Oxaliplatin, Sorafenib Tosylate, Temsirolimus,Thiotepa, Topotecan Hydrochloride, Vinblastine Sulfate, vincristinesulfate.
 18. A method of treatment, the method comprising: inserting acatheter into a bile duct to a region of the bile duct including acholangiocarcinoma; isolating the region of the bile duct including thecholangiocarcinoma by occluding the bile duct with a first occluder on adistal end region of the catheter and a second occluder on the distalend region of the catheter proximal to the first occluder; passing aguidewire through a lumen of the catheter to focally perforating atissue within the isolated region before delivering a therapeutic agent;delivering the therapeutic agent into the isolated region of the bileduct from out of an opening in a side wall of the catheter between thefirst occluder and the second occluder, whereby the therapeutic agentdiffuses into the cholangiocarcinoma within the bile duct.